- Conformational restriction design of thiophene-biphenyl-DAPY HIV-1 non-nucleoside reverse transcriptase inhibitors
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Conformational restriction is a promising strategy in the development of DAPY-type non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, eighteen thiophene-biphenyl-DAPY derivatives were designed and synthesized as potent HIV-1 NNRTIs in which halogen and methyl groups were introduced to explore the conformationally constrained effects. Molecular docking and dynamic simulation analysis indicated that substituents on different positions of the biphenyl ring induced different dihedral angles and binding conformations, further explaining their anti-viral activities. The 2′-fluoro and 3′-chloro substitutions could form electrostatic or halogen-bonding interactions with adjacent residues of the RT enzyme. The 2′-methyl group contributed to enlarge the dihedral angle of biphenyl ring and was positioned to a space-filling hydrophobic pocket. Notably, compounds 22 and 23 with two methyl groups exhibited potent biological activity against WT HIV-1-infected MT-4 cells (EC50 = 14 and 17 nM, respectively) and RT enzyme (EC50 = 27 and 42 nM, respectively). In particular, 23 exhibited much lower cytotoxicity (CC50 = 264.19 μM) and higher selectivity index (SI = 18,564) than etravirine. Taken together, a rational conformational model for further design of DAPYs is proposed, providing a new guidance for the development of NNRTIs.
- Sang, Yali,Han,Pannecouque, Christophe,De Clercq, Erik,Zhuang, Chunlin,Chen
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- Ligand-Based Design of Nondimethylphenyl-Diarylpyrimidines with Improved Metabolic Stability, Safety, and Oral Pharmacokinetic Profiles
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A series of nondimethylphenyl-diarylpyrimidines with much lower cytotoxicities than their dimethyl analogues were developed. Compound B13 with a difluorobiphenyl moiety showed the highest antiviral activity against WT, mutant strains, and RT. The hydrochloride form of B13 exhibited an improved water solubility of 5.6 μg/mL compared with ETR (?1 μg/mL), better stability in human and rat liver microsomes, and a great oral bioavailability of 44%, making it promising as a drug candidate. In addition, no apparent toxicity was observed in the acute toxicity assay (2 g/kg) and HE staining.
- Sang, Yali,Han, Sheng,Pannecouque, Christophe,De Clercq, Erik,Zhuang, Chunlin,Chen, Fener
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supporting information
p. 11430 - 11436
(2020/01/02)
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- Identification and structure-activity relationships of a novel series of estrogen receptor ligands based on 7-thiabicyclo[2.2.1]hept-2-ene-7-oxide
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To develop estrogen receptor (ER) ligands having novel structures and activities, we have explored compounds in which the central hydrophobic core has a more three-dimensional topology than typically found in estrogen ligands and thus exploits the unfilled space in the ligand-binding pocket. Here, we build upon our previous investigations of 7-oxabicyclo[2.2.1]heptene core ligands, by replacing the oxygen bridge with a sulfoxide. These new 7-thiabicyclo[2.2.1] hept-2-ene-7-oxides were conveniently prepared by a Diels-Alder reaction of 3,4-diarylthiophenes with dienophiles in the presence of an oxidant and give cycloadducts with endo stereochemistry. Several new compounds demonstrated high binding affinities with excellent ERα selectivity, but unlike oxabicyclic compounds, which are transcriptional antagonists, most thiabicyclic compounds are potent, ERα-selective agonists. Modeling suggests that the gain in activity of the thiabicyclic compounds arises from their endo stereochemistry that stabilizes an active ER conformation. Further, the disposition of methyl substituents in the phenyl groups attached to the bicyclic core unit contributes to their binding affinity and subtype selectivity.
- Wang, Pengcheng,Min, Jian,Nwachukwu, Jerome C.,Cavett, Valerie,Carlson, Kathryn E.,Guo, Pu,Zhu, Manghong,Zheng, Yangfan,Dong, Chune,Katzenellenbogen, John A.,Nettles, Kendall W.,Zhou, Hai-Bing
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experimental part
p. 2324 - 2341
(2012/05/20)
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- Calamitic bolaamphiphiles with (semi)perfluorinated lateral chains: Polyphilic block molecules with new liquid crystalline phase structures
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Novel bolaamphiphiles consisting of a rigid biphenyl unit, two terminal polar 1,2-diol units and laterally attached (semi)perfluorinated chains have been synthesized via palladium-catalyzed cross coupling reactions as the key step. The thermotropic liquid
- Cheng, Xiaohong,Prehm, Marko,Das, Malay Kumar,Kain, Jens,Baumeister, Ute,Diele, Siegmar,Leine, Dag,Blume, Alfred,Tschierske, Carsten
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p. 10977 - 10996
(2007/10/03)
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- Attempts to find a solution to the problem of atropisomer interconversion in 1,8-diarylnaphthalenes and 5,6-diarylacenaphthenes
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A series of sterically restricted 5,6-diarylacenaphthenes 5, 11, 12, 13 and 14 have been prepared via Suzuki crosscouplings of the appropriate boronic acids with 5,6-dibromoacenaphthene 3 in an attempt to prevent atropisomer interconversion in these systems. Attempts to further functionalise bis(p-methoxyphenyl) system 5 in the position ortho to the methyl ethers by Friedel-Crafts acylation or metallation were unsuccessful; however, two unexpected products were obtained, p,p′-Dimethoxybiphenyl 6 results from an unexpected rearrangement of 5 under strongly basic conditions and is dependent on the base used, whilst acylated derivative 7 results from a Friedel-Crafts acylation of the acenaphthene scaffold in the 3-position, rather than the desired functionalisation of the peri-aryl rings, presumably due to the difficulty in forming a tetrahedral intermediate. The oxygen functionality in 5 has been used, following methyl ether cleavage via diphenol 8 and allylation via 9, to demonstrate the viability of a double Claisen rearrangement yielding 11 after acetylation. However, the broad 1H NMR exhibited by 11 clearly showed that this system is not configurationally stable, hence steps were required to access more sterically demanding systems which would be configurationally stable. Molecular mechanics and semi-empirical simulations were carried out on related biaryl systems to determine if a single bulky substituent in the 3-position of the peri-aryl rings would be sufficient to prevent atropisomer interconversion. The modelling showed that the energies of the syn- and antiatropisomeric forms, e.g. for 12-14, were surprisingly similar. With the objective of preparing conformationally stable molecules in this class in mind, 12-14 were prepared in remarkable yield for such a hindered system. In spite of extensive attempts to determine whether 13 was configurationally stable, enantiomeric separation could not be achieved. Unsuccessful attempts were thus made to detect the presence of stable atropisomeric forms of 13 through the synthesis of bis(benzyl ether) 19, in which the benzylic protons could act as enantiotopic reporters. In addition mandelate ester 20 was prepared and it was shown by 1H NMR that a mixture of anti- and syn-diastereoisomers had been obtained. It was therefore concluded that steric groups in the 3-position of the peri-aryl rings cannot be used to prevent atropisomer interconversion in 1,8-diarylnaphthalenes and 5,6-diarylacenaphthenes. During attempts to access diphenols 18 and 24, other by-products were isolated, i.e. 21 and 25 respectively, resulting from a steric strain-induced 1,2-aryl shift.
- Steele, Melanie,Watkinson, Michael,Whiting, Andrew
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p. 588 - 598
(2007/10/03)
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